PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during Type 1 Diabetes

Kristen E. Pauken; Marc K. Jenkins; Miyuki Azuma; Brian T. Fife

doi:10.2337/db12-1475

PD-1, but not PD-L1, expressed by islet-reactive CD4⁺ T cells suppresses infiltration of the pancreas during Type 1 Diabetes

*Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA
^†Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA
^††Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Corresponding author: Brian T. Fife, bfife{at}umn.edu

Abstract

The inhibitory receptor PD-1 constrains Type 1 Diabetes (T1D) in the non-obese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4⁺ T cells during natural diabetes is not fully understood. To address this question we developed a novel model to investigate antigen-specific CD4⁺ T cells under physiological conditions in vivo. We transferred a low number of naïve CD4⁺ T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet⁺ IFNγ-producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not PD-L1, on the antigen-specific CD4⁺ T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node and pancreas. PD-1-deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4⁺ T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.

Keywords

Received October 24, 2012.
Accepted March 21, 2013.

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